Inhibition of the ubiquitin-proteasome pathway has been validated as a cornerstone of therapy for multiple myeloma by pre-clinical and clinical studies from our group and others. However, response rates among patients in the relapsed and refractory setting for bortezomib and carfilzomib, the two proteasome inhibitors that have garnered regulatory approvals, are less than 50% and 25%, respectively, and both are associated with significant toxicities. Moreover, patients are currently treated empirically, since no markers of proteasome inhibitor sensitivity have been identified, and even patients who initially respond eventually develop resistant disease through poorly understood mechanisms. Our preliminary studies have identified tight junction protein (TJP) 1 as a key modulator of proteasome inhibitor sensitivity through its ability to influence the balance in plasma cells between the proteasome load and capacity, a key determinant of myeloma responsiveness to proteasome inhibition. Furthermore, manipulation of TJP1 activity and expression is able to achieve chemosensitization and overcome chemoresistance to proteasome inhibitors. Together, these findings support our central hypothesis, which proposes that TJP1 is both a candidate biomarker of proteasome capacity and proteasome inhibitor sensitivity in myeloma, and a target for novel approaches to enhance the efficacy of this class of agents. To evaluate these possibilities, additional studies are proposed to further delineate the mechanisms by which TJP1 exerts its effects on proteasome subunit synthesis, and therefore capacity. In addition, genomic studies will be performed in association with prospective cooperative group trials of bortezomib and carfilzomib to validate the possibility that TJP1 expression may help to identify patients who are most and least likely to benefit from proteasome inhibitor-based therapy. Finally, approaches to enhance the activity of TJP1, including inhibitors of the epidermal growth factor receptor and Janus kinases/signal transducer and activator of transcription 3, and also approaches to enhance TJP1 expression, such as with hypomethylating agents, will be evaluated for their ability to induce chemosensitization, and overcome chemoresistance in cell lines, primary samples, and physiologically relevant in vivo murine models.